14-37591820-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004496.5(FOXA1):​c.964G>A​(p.Gly322Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

FOXA1
NM_004496.5 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29
Variant links:
Genes affected
FOXA1 (HGNC:5021): (forkhead box A1) This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15926015).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXA1NM_004496.5 linkc.964G>A p.Gly322Ser missense_variant Exon 2 of 2 ENST00000250448.5 NP_004487.2 P55317-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXA1ENST00000250448.5 linkc.964G>A p.Gly322Ser missense_variant Exon 2 of 2 1 NM_004496.5 ENSP00000250448.3 P55317-1
FOXA1ENST00000545425.2 linkn.1079G>A non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.66e-7
AC:
1
AN:
1305270
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
635646
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.60e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 10, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.964G>A (p.G322S) alteration is located in exon 2 (coding exon 2) of the FOXA1 gene. This alteration results from a G to A substitution at nucleotide position 964, causing the glycine (G) at amino acid position 322 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.063
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.29
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.66
T
M_CAP
Pathogenic
0.61
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
0.84
L
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
0.16
N
REVEL
Benign
0.16
Sift
Benign
0.58
T
Sift4G
Benign
1.0
T
Polyphen
0.0090
B
Vest4
0.052
MutPred
0.24
Gain of glycosylation at G322 (P = 0.0136);
MVP
0.65
ClinPred
0.12
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.087
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-38061025; API